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Antimicrobial Agents and Chemotherapy, February 2006, p. 469-473, Vol. 50, No. 2
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.2.469-473.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Pharmacodynamic Activity of Amphotericin B Deoxycholate Is Associated with Peak Plasma Concentrations in a Neutropenic Murine Model of Invasive Pulmonary Aspergillosis

Nathan P. Wiederhold,3,4* Vincent H. Tam,1 Jingduan Chi,1 Randall A. Prince,1,2 Dimitrios P. Kontoyiannis,1,2 and Russell E. Lewis1,2

The University of Houston College of Pharmacy,1 The University of Texas M. D. Anderson Cancer Center, Houston,2 The University of Texas at Austin College of Pharmacy, Austin,3 The University of Texas Health Science Center at San Antonio, San Antonio, Texas4

Received 19 July 2005/ Returned for modification 13 September 2005/ Accepted 15 November 2005

We conducted a dose fractionation study of neutropenic, corticosteroid-immunosuppressed mice to characterize the pharmacodynamic/pharmacokinetic (PK/PD) parameter most closely associated with amphotericin B (AMB) efficacy in the treatment of invasive pulmonary aspergillosis. Pharmacokinetic parameter estimates were determined by a nonparametric population pharmacokinetic analysis of plasma drug concentrations following single intraperitoneal doses (0.25, 1.0, and 3.0 mg/kg of body weight) of amphotericin B deoxycholate. Three dosage groups (0.5, 0.75, and 1.0 mg/kg) fractionated into three dosing intervals (every 8 h [q8h], q24h, or q72h) were tested to discriminate between the PK/PD parameters (the ratio of maximum concentration of drug in serum [Cmax]/MIC, the ratio of area under the concentration-time curve/MIC, and percentage of time above MIC) most closely associated with AMB efficacy over a range of clinically achievable exposures in humans. The efficacy of each regimen was determined by quantitative PCR and survival. Reductions in pulmonary fungal burden and improvements in survival were maximized at the highest peak plasma concentrations in each of the dosage groups. Reductions in pulmonary fungal burden and increased survival were most closely associated with Cmax/MIC, with maximal activity occurring as the Cmax/MIC approached 2.4. In our model, Cmax/MIC is the PK/PD parameter most closely associated with efficacy in the treatment of invasive pulmonary aspergillosis. These data predict that less frequently administered, higher dosages of AMB would optimize efficacy.

* Corresponding author. Mailing address: The University of Texas at Austin College of Pharmacy, UTHSCSA, Clinical Pharmacy MSC 6220, 7703 Floyd Curl Dr., San Antonio, TX 78229. Phone: (210) 567-8340. Fax: (210) 567-8328. E-mail: wiederholdn{at}uthscsa.edu.

Antimicrobial Agents and Chemotherapy, February 2006, p. 469-473, Vol. 50, No. 2
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.2.469-473.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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